There are several basic approaches to combat viral infections (apart from the treatment of individual symptoms): (1) vaccination—induction of immunity to prevent viral infection, (2) targeting viral replication cycle with small molecule agents or therapeutic antibodies, and (3) activation of host response (primarily, with the use of interferons or interferon inducers) WAGNER, E. K., et al. Basic Virology. 2nd edition. Oxford: Blackwell Publishing, 2004. ISBN 1405103469. p. 96-116.
Each of the mentioned approaches has certain limitations or disadvantages. Vaccination is only expedient for vaccine-preventable infections; natural variability of the pathogen (e.g., influenza virus) can minimize the efficacy of vaccination; finally, vaccination is infrequently associated with undesirable reactions. Each therapeutic agent targeting viral replication cycle is effective in only a narrow range of disease conditions caused by pathogens sharing common molecular target; the use of such agents can be associated with the development of resistance and/or undesirable reactions. It is also very important to take into consideration that severity and duration of the conditions caused by viruses depend on two groups of factors: virus concentrations in the target organs (with corresponding direct cytopathic effect) linked with the rate of viral clearance on the one hand and adequacy of host innate and adaptive immune response on the other hand. Thus, even a relatively low dose of a highly pathogenic virus can cause a very severe disease, the severity being often the result of ‘cytokine storm’ (SZRETTER, K. J., et al. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol. 2007, vol. 81, no. 6, p. 2736-44.) caused by a kind of inopportune reaction of the host defence.
The agents capable of activating the host response (biological response modifiers, immunomodulators) seem to be a promising group of antiviral therapeutics with regard to their ‘natural’ mode of action and independence on the particular cause of viral infection. This group of therapeutics can be exemplified by interferons (e.g., pegylated interferon alpha-2a), imiquimod (interferon inducer acting as an agonist of toll-like receptor 7), tilorone (orally active interferon inducer). However, all known interferon preparations have significant adverse effects, and synthetic interferon inducers have either problems of safety or bioavailability.
There are numerous therapeutic agents comprising full antibodies or antibody fragments designed for the treatment of different diseases (Brekke O H, Sandlie I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov. 2003 January; 2(1):52-62.). Several of them are designed for diseases caused by viruses: for example, in HIV infection, antibody fragments are proposed to block a viral protein gp120 (Danishefsky et al., US patent application 20060229432, published Oct. 12, 2006); in respiratory syncytial virus (RSV) infection monoclonal antibodies are known (palivizumab) to target RSV, prevent, treat or ameliorate symptoms associated with an RSV infection. The mentioned agents are intended to block/inhibit their target molecule, they are administered in substantial doses (at least 0.001 mg/kg). Theoretically, the prior art includes oral administration, but the existing products cannot be used in oral dosage forms due to poor bioavailability provided by this route for protein based medicine. Less numerous peroral pharmaceutical formulations based on antibodies or antibody fragments (US patent applications 20060002927 (10513109), 20050136103 (10942300), 20030153022 (10287821), etc.) target a molecule within gastrointestinal tract or a bacterial exogenous peptide, and are administered in substantial doses essential to achieve certain concentration in the gastrointestinal tract and block their target
Apart from antiviral agents, prior art covers mostly antibodies aimed at molecular targets that are up-regulated in a particular disease condition with the intention of lowering their level to normality. An example closest to the subject of the present application is the US patent application US20060115475 by Carton et al., “Toll like receptor 3 antagonists, methods and uses”. It discloses anti-TLR3 (Toll like receptor type 3) antibodies effective in the treatment and prevention of inflammatory conditions, including those associated with infections, by antagonizing TLR3 to inhibit cellular production of pro-inflammatory cytokines. As can be concluded from description of that application, the authors propose to use monoclonal antibodies directed to one of the numerous epitopes of extracellular ligand-binding domain of TLR3 which has the length of 703 amino acids. These antibodies are injected intraperitoneally after a sub-lethal influenza infection, shortly before (prophylactic injection) and shortly after (therapeutic injection) a challenge with S. pneumoniae, in order to prevent septic shock caused by the bacterial pathogen on the background of a subsided influenza infection. Therefore, the US20060115475 application rather focuses on prevention and treatment of lethal inflammatory complications of bacterial infections by antagonizing extracellular domain of TLR3, than demonstrates any prophylactic or therapeutic use of anti-TLR3 antibodies in a viral infection.
Another general approach is the use of antibodies or antibody fragments to target markers specifically expressed by malignant or otherwise diseased cells. Mimetics (receptor agonists) based on antibodies are known in prior art, but none of them is actually used in practice.
In addition to the above-mentioned antiviral approaches and numerous symptomatic therapeutics for viral infections, there are several homeopathic medicinal agents registered for prevention and treatment of viral infections, primarily influenza and common cold. Most of them are individually prescribed by doctor on the basis of patient specific symptoms according to the homeopathic tradition. However, several products claim universal indications to be effective in upper respiratory infections. Most noteworthy of them are Oscillococcinum (marketed in France, several other EU states and North America) and Anaferon (marketed in Russia and several neighbouring states, but not in the EU). Oscillococcinum is made from heart and liver of duck (homeopathic dilution K200), Anaferon is made from antibodies to interferon gamma (mixture of homeopathic dilutions (RU WO2005000350 A (EPSHTEIN OI) 6 Jan. 2005). Whereas homeopathic therapeutics are generally recognized as safe, the efficacy of the mentioned products remains uncertain, at least, judging from the published studies. For Oscillococcinum there is no published evidence of efficacy in animal models of viral infections, and its clinical benefit in the treatment of influenza and influenza-like syndrome is regarded as very moderate (VICKERS, A. J., et al. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. Cochrane Database Syst Rev. 2006 July, vol. 19, no. 3, p.CD001957.). For Anaferon, animal efficacy data is published (SERGEEV, A. N., et al. [Antiviral activity of oral ultralow doses of antibodies to gamma-interferon: experimental study of influenza infection in mice]. Antibiot Khimioter. 2004, vol. 49, no. 11, p. 7-11.; SUSLOPAROV, M. A., et al. [Efficacy of therapeutic and prophylactic actions of ultralow doses of antibodies to gamma-interferon in experimental murine model of herpes virus]. Antibiot Khimioter. 2004, vol. 49, no. 10, p. 3-6.); the benefits of the product in human clinical trials can only be estimated from abstracts of scientific conferences.
A general approach was proposed for manufacturing homeopathic products using “antibodies to an antigen acting as a direct cause of a pathological syndrome or involved in regulation of mechanisms of its formation” (EP1295606 A (EPSHTEIN O. I.) 26 Mar. 2003). But the cited patent application does not suggest any clue to choosing particular molecular target in a particular disease. When one considers that hundreds of proteins are involved in the regulation of host defence against viral infections (each of the proteins including dozens of epitopes to raise antibodies to), one has to select the best drug candidate out of thousands of possible options.